There are compelling research opportunities for Parkinson's disease (PD) therapies. While L-dopa provides an initial relief, there is a need for alternative strategies to deal with the continued loss of dopaminergic (DA) neurons, axons and terminals. We have a functional collaborative scientific group centered at McLean Hospital, Harvard Primate Center and Massachusetts General Hospital that can investigate neuroprotective, neuromodulatory and neural transplantation approaches for PD. We will use animal models, including MPTP-treated primates with loss of dopamine cells, synapses and function. This work is synergistically linked in four projects: Project 1. A neurophilin ligand induced prevention of dopaminergic degeneration induced by MPTP in the primate. Two paradigms are tested; a) neuroprotection by a neurophilin ligand to reduce the loss of dopamine terminals and b) a regeneration paradigm with post neurophilin ligand treatment to regenerate remaining DA terminals. Project 2. We will test neuronal replacement by fetal dopamine cells into the striatum, the subthalamic nucleus and the substantia nigra in a primate model of PD. We hypothesize that a full reinnervation with novel dopaminergic fibers in these regions will fully restore the dysfunctional circuitry responsible for PD. Project 3. By generating dopaminergic neurons from blastoma stage stem cells, we can obtain renewable cells to be transplanted for functional tests into animal models of parkinsonism. These stem cell derived dopaminergic neurons will be compared in function to these derived from phenotypically normal embryonic fetal cells. Project 4 is an educational component of the grant, with a major commitment to training new scientists PD. These projects are supported by 2 Cores that further integrate these projects; namely, an Administrative Core that supports the research teams involved, and the Imaging Core involving functional MRI and PET scans and analysis. In summary, we feel this compelling research collaboration on novel realistic approaches to PD treatment is of exceptional value. The allocation of these resources will test major scientific hypotheses in protecting, repairing or replacing the dopaminergic system responsible for the signs of PD.